Janssen Announces 96-week Results of Phase 3b Study Demonstrating the Continued Safety and Efficacy of Long-acting HIV Treatment of Rilpivirine and Cabotegravir

CORK, IRELAND, March 6, 2021 – The Janssen Pharmaceutical Companies of Johnson & Johnson today presented positive long-term data from the global Phase 3b trial of the first complete, long-acting (LA), two-drug injectable regimen (consisting of Janssen’s rilpivirine and ViiV Healthcare’s cabotegravir) for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults. The 96-week findings of the Antiretroviral Therapy as Long-Acting Suppression Every 2 Months (ATLAS-2M) trial confirmed the primary endpoint, met at Week 48, and met the secondary endpoint, showing efficacy of both monthly dosing and every 2-month dosing over the long-term in virologically suppressed adults with HIV-1.1 These data were presented at the 2021 Conference on Retroviruses and Opportunistic Infections (CROI). The every two-months dosing regimen is under investigation and is not approved in the U.S. or Canada.

“Johnson & Johnson has been in the fight against HIV for decades – and our commitment to driving the innovation needed to help make HIV history is as strong as ever,” said Ruxandra Draghia-Akli, M.D., Ph.D., Global Head, Global Public Health Research & Development, Janssen Research & Development, LLC. “The data from the ATLAS-2M study is further evidence that this long-acting injectable regimen could offer a promising new treatment option, as appropriate, for people living with HIV – and we are extremely proud of the scientific advancement that this represents.”

The global Phase 3b ATLAS-2M study met its primary endpoint at Week 48, finding that every-eight-week (two-months) dosing of the LA regimen was noninferior to every-four-week (monthly) dosing. Data from the study showed that the proportions of patients with a viral load ≥50 copies/mL were similar between the two arms: 1.7% (9/522) in the every two-months arm and 1.0% (5/523) in the once-monthly arm (adjusted difference: 0.8%, 95% confidence interval [CI]: -0.6, 2.2).2 Week 96 findings reinforced the primary endpoint: the efficacy of every two-month dosing was noninferior to monthly dosing of long-acting cabotegravir and rilpivirine, with 2.1% (11/522) and 1.1% (6/523) of participants, respectively, having HIV-1 RNA ≥50 c/mL (adjusted difference: 1.0%, 95% confidence interval [CI]: -0.6-2.5).1 The 96-week ATLAS-2M study secondary endpoint showed that rates of virologic suppression were similar between the two arms, with 91.0% (475/522) of participants in the every two-month dosing arm and 90.2% (472/523) in the monthly dosing arm achieving HIV-1 RNA <50 c/mL (adjusted difference: 0.8%, 95% CI: -2.8-4.3).1

Week 96 findings reported confirmed virologic failures (CVFs), defined as two consecutive viral loads ≥200 c/mL, in 1.7% (9/522) of participants in the every two-month dosing arm and 0.4% (2/523) in the monthly dosing arm.1 The rate of CVF overall was 1%, with only one participant in the every two-month dosing arm meeting the criterion in the second year of therapy. This patient developed a rilpivirine resistance-associated mutation (RAM), Y181C, and no integrase inhibitor (INI) RAMS.1

Safety profiles were comparable between the two treatment arms, with no new safety signals identified since the 48-week analysis.1,2 Injection site reactions (ISRs) were the most common adverse event (AE) (16% [74/473] in the every two-month dosing arm and 12% [54/468] in the monthly dosing arm), with one leading to withdrawal between weeks 48 and 96.1 Most ISRs (99%) were mild or moderate and self-resolving, with a median duration of three days. Over the entire 96 weeks, in the every two-month dosing arm, 1% (7/522) of participants discontinued due to ISRs, vs 2% (11/523) in the monthly dosing arm.1

The most common non-ISR drug-related AEs were pyrexia and fatigue. Grade ≥ 3 adverse events were seen in 11% (57/522) of participants in the every 2-month arm and 12% (65/523) in the once monthly arm. Adverse events leading to withdrawal were seen in 3% (18/522) in the every two-month arm and 4% (19/523) in the once monthly arm.1

Data previously reported show that ninety-eight percent of participants preferred the every two-month, long-acting treatment over their daily, oral therapy. Patient preference data was measured using a single-item questionnaire at Week 48.2

This novel regimen was co-developed as part of a collaboration with ViiV Healthcare and builds on Janssen’s 25-year commitment to make HIV history. It is licensed as a once-monthly treatment in Canada and the U.S. under the name CABENUVA, and a supplemental New Drug Application (sNDA) has been submitted to the U.S. Food and Drug Administration for expanding the use of CABENUVA as an HIV treatment to include every two-month dosing.3 The every two-month regimen is also under review by Health Canada.

The every two-month regimen of Janssen’s REKAMBYS® (rilpivirine injection) in combination with ViiV Healthcare’s VOCABRIA® (cabotegravir injection), in addition to the once-monthly regimen, was approved by the European Commission in December 2020. Both the once-monthly and every two-month dosing regimens (co-packaged as CABENUVA) were also approved by Australia Therapeutic Goods Administration in February 2021. Regulatory reviews continue in Switzerland, with several additional submissions planned throughout 2021 globally. ViiV Healthcare is the marketing authorization holder for CABENUVA in the U.S., Australia and Canada.

About ATLAS-2M (NCT03299049)
The ATLAS-2M study is an ongoing Phase 3b, randomized, open-label, active-controlled, multicenter, parallel-group, non-inferiority study designed to assess the non-inferior antiviral activity and safety of a long-acting, two-drug injectable regimen (consisting of Janssen’s rilpivirine and ViiV Healthcare’s cabotegravir) administered every eight weeks (two-months) compared to every four weeks (once-monthly) dosing over a 48-week and 96-week treatment period in 1,045 adults living with HIV-1. Participants were required to be virologically suppressed for six months or greater, on first or second antiretroviral regimen, with no prior virologic failure. The primary outcome measure for the study is the proportion of participants with HIV-1 RNA ≥50 c/mL at Week 48 and Week 96 using the FDA Snapshot algorithm (intent-to-treat exposed [ITT-E] population). For further information please see https://clinicaltrials.gov/ct2/show/NCT03299049

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About rilpivirine
The oral formulation of rilpivirine is also authorised for the treatment of HIV-1 infection in combination with other antiretroviral agents in antiretroviral treatment-naïve patients 12 years of age and older and weighing at least 35 kg with a viral load ≤100,000 HIV RNA copies/mL.

Rilpivirine long-acting is a prolonged-release suspension for IM injection developed by Janssen Sciences Ireland Unlimited Company, one of the Janssen Pharmaceutical Companies of Johnson & Johnson.

Rilpivirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that works by interfering with an enzyme called reverse transcriptase, which in turn stops the virus from multiplying.

About cabotegravir
Cabotegravir is an integrase strand transfer inhibitor (INSTI) developed by ViiV Healthcare for the treatment of HIV-1 in virologically suppressed adults. It is being evaluated in combination with injectable rilpivirine as a long-acting formulation.

INSTIs inhibit HIV replication by preventing the viral DNA from integrating into the genetic material of human immune cells (T-cells). This step is essential in the HIV replication cycle and is also responsible for establishing chronic infection.

Administration and dosing of rilpivirine and cabotegravir
Rilpivirine injection used in combination with cabotegravir injection is the first complete long-acting regimen dosed every month (or every 2-months, in the European Union and Australia) for virologically suppressed people living with HIV-1. Rilpivirine and cabotegravir injections are administered as two gluteal intramuscular (IM) injections by a healthcare professional at the same appointment. Prior to the initiation of the injections, rilpivirine and cabotegravir oral tablets are taken for approximately one month (at least 28 days) to assess tolerability to the medicines.

Important Safety Information for CABENUVA
CABENUVA is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine.

CONTRAINDICATIONS
· Do not use CABENUVA in patients with previous hypersensitivity reaction to cabotegravir or rilpivirine.
· Do not use CABENUVA in patients receiving carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, systemic dexamethasone (>1 dose), and St John’s wort.

WARNINGS AND PRECAUTIONS

Hypersensitivity Reactions:
· Hypersensitivity reactions, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported during postmarketing experience with rilpivirine-containing regimens. While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries.
· Serious or severe hypersensitivity reactions have been reported in association with other integrase inhibitors and could occur with CABENUVA.
· Discontinue CABENUVA immediately if signs or symptoms of hypersensitivity reactions develop. Clinical status, including liver transaminases, should be monitored and appropriate therapy initiated. Prescribe the oral lead-in prior to administration of CABENUVA to help identify patients who may be at risk of a hypersensitivity reaction.

Post-Injection Reactions:
· Serious post-injection reactions (reported in less than 1% of patients) were reported within minutes after the injection of rilpivirine, including dyspnea, agitation, abdominal cramping, flushing, sweating, oral numbness, and changes in blood pressure. These events may have been associated with inadvertent (partial) intravenous administration and began to resolve within a few minutes after the injection.
· Carefully follow the Instructions for Use when preparing and administering CABENUVA to avoid accidental intravenous administration. Observe patients briefly (approximately 10 minutes) after the injection. If a post-injection reaction occurs, monitor and treat as clinically indicated.

Hepatotoxicity:
· Hepatotoxicity has been reported in patients receiving cabotegravir or rilpivirine with or without known pre-existing hepatic disease or identifiable risk factors.
· Patients with underlying liver disease or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations.
· Monitoring of liver chemistries is recommended and treatment with CABENUVA should be discontinued if hepatotoxicity is suspected.

Depressive Disorders:
· Depressive disorders (including depressed mood, depression, major depression, mood altered, mood swings, dysphoria, negative thoughts, suicidal ideation or attempt) have been reported with CABENUVA or the individual products.
· Promptly evaluate patients with depressive symptoms.

Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions:
· The concomitant use of CABENUVA and other drugs may result in known or potentially significant drug interactions (see Contraindications and Drug Interactions).
· Rilpivirine doses 3 and 12 times higher than the recommended oral dosage can prolong the QTc interval. CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes.

Long-Acting Properties and Potential Associated Risks with CABENUVA:
· Residual concentrations of cabotegravir and rilpivirine may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer). Select appropriate patients who agree to the required monthly injection dosing schedule because non-adherence to monthly injections or missed doses could lead to loss of virologic response and development of resistance.
· To minimize the potential risk of developing viral resistance, it is essential to initiate an alternative, fully suppressive antiretroviral regimen no later than 1 month after the final injection doses of CABENUVA. If virologic failure is suspected, switch the patient to an alternative regimen as soon as possible.

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ADVERSE REACTIONS
The most common adverse reactions (incidence ≥2%, all grades) with CABENUVA were injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash.

DRUG INTERACTIONS
· Refer to the applicable full Prescribing Information for important drug interactions with CABENUVA, Vocabria, or rilpivirine.
· Because CABENUVA is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended.
· Drugs that are strong inducers of UGT1A1 or 1A9 are expected to decrease the plasma concentrations of cabotegravir. Drugs that induce or inhibit CYP3A may affect the plasma concentrations of rilpivirine.
· CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes.

USE IN SPECIFIC POPULATIONS
· Pregnancy: There are insufficient human data on the use of CABENUVA during pregnancy to adequately assess a drug-associated risk for birth defects and miscarriage. Discuss the benefit-risk of using CABENUVA during pregnancy and conception and consider that cabotegravir and rilpivirine are detected in systemic circulation for up to 12 months or longer after discontinuing injections of CABENUVA. An Antiretroviral Pregnancy Registry has been established.
· Lactation: The CDC recommends that HIV1−infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Breastfeeding is also not recommended due to the potential for developing viral resistance in HIV-positive infants, adverse reactions in a breastfed infant, and detectable cabotegravir and rilpivirine concentrations in systemic circulation for up to 12 months or longer after discontinuing injections of CABENUVA.

Please see full Prescribing Information.

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Important Safety Information (EU)
For the EU, please refer to the full product and prescribing information for:

REKAMBYS®: https://www.ema.europa.eu/en/documents/product-information/rekambys-epar-product-information_en.pdf

VOCABRIA®: https://www.ema.europa.eu/en/documents/product-information/vocabria-epar-product-information_en.pdf

EDURANT®: https://www.ema.europa.eu/en/documents/product-information/edurant-epar-product-information_en.pdf /

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About the Janssen Pharmaceutical Companies of Johnson & Johnson
At Janssen, we’re creating a future where disease is a thing of the past. We’re the Pharmaceutical Companies of Johnson & Johnson, working tirelessly to make that future a reality for patients everywhere by fighting sickness with science, improving access with ingenuity, and healing hopelessness with heart. We focus on areas of medicine where we can make the biggest difference: Cardiovascular & Metabolism, Immunology, Infectious Diseases & Vaccines, Neuroscience, Oncology, and Pulmonary Hypertension.

Learn more at www.janssen.com and follow us at www.twitter.com/JanssenGlobal and www.twitter.com/JanssenUS. Janssen Sciences Ireland Unlimited Company is part of the Janssen Pharmaceutical Companies of Johnson & Johnson.

To learn more about Janssen’s commitment to the prevention and treatment of HIV, please visit jnj.com/HIV.

Cautions Concerning Forward-Looking Statements
This press release contains “forward-looking statements” as defined in the Private Securities Litigation Reform Act of 1995 regarding rilpivirine and development of potential preventive and treatment regimens for HIV. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen Sciences Ireland Unlimited Company, any of the other Janssen Pharmaceutical Companies and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; manufacturing difficulties and delays; competition, including technological advances, new products and patents attained by competitors; challenges to patents; product efficacy or safety concerns resulting in product recalls or regulatory action; changes in behavior and spending patterns of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson’s Annual Report on Form 10-K for the fiscal year ended January 3, 2021, including in the sections captioned “Cautionary Note Regarding Forward-Looking Statements” and “Item 1A. Risk Factors,” and in the company’s most recently filed Quarterly Report on Form 10-Q, and the company’s subsequent filings with the Securities and Exchange Commission. Copies of these filings are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. None of the Janssen Pharmaceutical Companies nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.

References
1 Jaeger H et al. Week 96 efficacy and safety of cabotegravir + rilpivirine every 2 months: ATLAS-2M. Presented at the Conference on Retroviruses and Opportunistic Infections (CROI) Virtual; March 6-10 2021.

2 Overton E et al. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study. The Lancet. 2020;396(10267):1994-2005.

3 CABENUVA (cabotegravir, rilpivirine) Prescribing Information. US Approval January 2021.


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